Identification of downstream targets of the Bone Morphogenetic Protein pathway in the <i>Drosophila</i> nervous system

Kim, Nam Chul; Marqués, Guillermo

doi:10.1002/dvdy.22368

Cited by 23 publications

(24 citation statements)

References 72 publications

(95 reference statements)

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“…Bursb expression was reduced to 31±19% (n67) of controls (n84; P<0.0001). This finding was recently independently confirmed by microarray analysis of wit mutants, which showed a similar downregulation of Bursb (Kim and Marques, 2010). Burs expression was only subtly downregulated in wit mutants, to 82±28% (n82) of controls (n88; P0.01).…”

Section: Ccap Mip and Bursb Expression In Ccap-ens Is Bmp Dependentsupporting

confidence: 54%

Retrograde BMP signaling controls Drosophila behavior through regulation of a peptide hormone battery

Veverytsa

Allan

2011

Development

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Retrograde BMP signaling in neurons plays conserved roles in synaptic efficacy and subtype-specific gene expression. However, a role for retrograde BMP signaling in the behavioral output of neuronal networks has not been established. Insect development proceeds through a series of stages punctuated by ecdysis, a complex patterned behavior coordinated by a dedicated neuronal network. In Drosophila, larval ecdysis sheds the old cuticle between larval stages, and pupal ecdysis everts the head and appendages to their adult external position during metamorphosis. Here, we found that mutants of the type II BMP receptor wit exhibited a defect in the timing of larval ecdysis and in the completion of pupal ecdysis. These phenotypes largely recapitulate those previously observed upon ablation of CCAP neurons, an integral subset of the ecdysis neuronal network. Here, we establish that retrograde BMP signaling in only the efferent subset of CCAP neurons (CCAP-ENs) is required to cell-autonomously upregulate expression of the peptide hormones CCAP, Mip and Bursicon β. In wit mutants, restoration of wit exclusively in CCAP neurons significantly rescued peptide hormone expression and ecdysis phenotypes. Moreover, combinatorial restoration of peptide hormone expression in CCAP neurons in wit mutants also significantly rescued wit ecdysis phenotypes. Collectively, our data demonstrate a novel role for retrograde BMP signaling in maintaining the behavioral output of a neuronal network and uncover the underlying cellular and gene regulatory substrates.

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Section: Ccap Mip and Bursb Expression In Ccap-ens Is Bmp Dependentsupporting

confidence: 54%

Retrograde BMP signaling controls Drosophila behavior through regulation of a peptide hormone battery

Veverytsa

Allan

2011

Development

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“…These data suggest that muscle-secreted Gbb activates the BMP receptor complex at the NMJ, inducing accumulation of pMad in the motoneuron nuclei and growth of the synaptic terminal (McCabe et al, 2003). Transcriptional targets of the BMP pathway in motoneurons have recently been described (Ball et al, 2010;Kim and Marqués, 2010) confirming its role in regulation of gene expression.…”

Section: Introductionmentioning

confidence: 71%

“…In Drosophila motoneurons the BMP pathway is activated at the synaptic terminal but ultimately results in regulation of transcription in the nucleus (Ball et al, 2010;Kim and Marqués, 2010), thus this signaling pathway is dependent on long-range signal propagation. Our results indicate that signal relay is mediated by a signaling endosome containing an activated receptor complex formed by Wit and Tkv.…”

Section: Discussionmentioning

confidence: 99%

Relay of retrograde synaptogenic signals through axonal transport of BMP receptors

Smith

Machamer

Kim

et al. 2012

Journal of Cell Science

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SummaryNeuronal function depends on the retrograde relay of growth and survival signals from the synaptic terminal, where the neuron interacts with its targets, to the nucleus, where gene transcription is regulated. Activation of the Bone Morphogenetic Protein (BMP) pathway at the Drosophila larval neuromuscular junction results in nuclear accumulation of the phosphorylated form of the transcription factor Mad in the motoneuron nucleus. This in turn regulates transcription of genes that control synaptic growth. How BMP signaling at the synaptic terminal is relayed to the cell body and nucleus of the motoneuron to regulate transcription is unknown. We show that the BMP receptors are endocytosed at the synaptic terminal and transported retrogradely along the axon. Furthermore, this transport is dependent on BMP pathway activity, as it decreases in the absence of ligand or receptors. We further demonstrate that receptor traffic is severely impaired when Dynein motors are inhibited, a condition that has previously been shown to block BMP pathway activation. In contrast to these results, we find no evidence for transport of phosphorylated Mad along the axons, and axonal traffic of Mad is not affected in mutants defective in BMP signaling or retrograde transport. These data support a model in which complexes of activated BMP receptors are actively transported along the axon towards the cell body to relay the synaptogenic signal, and that phosphorylated Mad at the synaptic terminal and cell body represent two distinct molecular populations.

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“…Normally p-Mad localization is observed in motor neuron cell bodies, axons and NMJs [72]–[73], [43], [39], [74]–[75] (Figure 4), and disruption of the dynein complex by either loss of roblk (Figure 4) or excess of DN Glued [10] perturbed BMP signaling, as measured by p-Mad. Further, a direct link between the activation of BMP signaling and the growth of presynaptic arbors has also been identified [76]–[77]. Ball et al demonstrated that Trio, the Rho-type guanyl-nucleotide exchange factor (GEF) is under the transcriptional control of BMP signaling and, together with Rac, is involved in presynaptic growth and regulation of neurotransmitter release [78].…”

Section: Discussionmentioning

confidence: 99%

Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

et al. 2014

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Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases.

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Identification of downstream targets of the Bone Morphogenetic Protein pathway in the Drosophila nervous system

Cited by 23 publications

References 72 publications

Retrograde BMP signaling controls Drosophila behavior through regulation of a peptide hormone battery

Retrograde BMP signaling controls Drosophila behavior through regulation of a peptide hormone battery

Relay of retrograde synaptogenic signals through axonal transport of BMP receptors

Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

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